EPIG-06: ATRX DEFICIENCY PROMOTES MIGRATORY BEHAVIOR IN GLIOMA CELLS OF ORIGIN BY DYSREGULATING GENOME-WIDE CHROMATIN ACCESSIBILITY AND MODULATING TRANSCRIPTIONAL PROGRAMS

Comprehensive genomic profiling in cancer continues to reveal frequent alterations in epigenetic regulators, firmly implicating chromatin biology in the oncogenic process. We and others recently found that inactivating mutations in the SWI/SNF family member ATRX represent defining molecular alterations in diffusely infiltrating gliomas, where they invariably pair with mutations in TP53 and IDH1/2. A number of studies have linked ATRX deficiency to a wide spectrum of physiological dysfunction, including aberrant gene regulation, abnormal telomere maintenance, genomic instability, and aneuploidy. Nevertheless, the molecular mechanism(s) by which ATRX deficiency promotes oncogenesis are still largely unestablished. To understand the role of Atrx loss-of-function mutations in gliomagenesis, we inactivated Atrx in Tp53-/- murine neuroepithelial progenitor cells (NPCs), which have been implicated as potential glioma cells of origin by several prior studies. Interestingly, Atrx loss induced NPCs to stop growing as neurospheres and adopt an adherent phenotype, while also exhibiting significantly increased cellular motility by transwell migration assay, the latter an established pathogenic feature of diffusely infiltrating gliomas. These phenotypes correlated with altered gene expression profiles involving molecular networks implicated in development, regulation of signal transduction, and cellular motility and invasion. Integrating these transcriptional changes with shifts in chromatin accessibility occurring with Atrx deficiency and genome-wide Atrx distribution, as determined by ChIP-seq, revealed highly significant spatial correlations between differentially expressed genes, regions of altered chromatin compaction, and genomic sites normally occupied by Atrx. Taken together, these findings demonstrate that Atrx deficiency induces widespread disruptions in chromatin organization, which in turn lead to dramatic shifts in gene expression and acquisition of disease-relevant phenotypes in putative glioma cells of origin. We are now in the process of identifying and characterizing the precise transcriptional and epigenetic events mediating the acquisition of Atrx-dependent behaviors in NPCs.